The hTau mouse offers an opportunity to examine some of the most basic questions regarding the development of tau pathology. In Project 4, we will test the hypothesis that the accumulation of hyperphosphorylated tau in CA1 pyramidal neurons will impair the synaptic physiology of these cells, by measuring basal synaptic transmission and long term potentiation. Hippocampii from hemibrains of hTau mice of four defined ages will be examined, and the results will be compared to those obtained from age-matched mouse plus human tau mice (8c) and non-transgenic mice, all littermates. The physiology of specific aim 1 will be complemented by biochemical and immunohistochemical studies of glutamate receptors, their phosphorylation status, and levels of associated proteins, in particular calcium-calmodulin dependent protein kinase II (CamKII). The activity of CamKII will be examined and its association with human tau determined. These analyses will be performed on the other half of the brains used for electrophysiology. We will attempt to directly test the hypothesis that it is tau hyperphosphorylation by either cdk5 or GSK3beta that impairs the synaptic physiology of CA1 neurons in hTau mice. Project 5 will define doses and routes of administration of lithium (a GSK3 inhibitor) and roscovitine (a cdk5 inhibitor) that reduce tau phosphorylation in the hTau mice. The same doses and routes of administration will be used to assess the effects of these treatments on synaptic physiology and biochemistry. The effects of a tau aggregation inhibitor, NN13, will also be investigated, if work under project 5 suggests this is a viable treatment for the hTau mouse. We will test the hypothesis that elevation of Abeta concentrations in hTau mice accelerates the appearance of defects in synaptic transmission. Abeta concentrations will be elevated by breeding in the Tg2576 APP transgene, and both physiology and biochemistry will be performed on APP+/hTau+, APP+/hTau-, APP-/hTau+ and APP-/hTau- mice of different ages. In this program project application, a wide variety of techniques are being employed to characterize the molecular details of the tauopathy, as well as the detailed morphology of specific neuronal populations. Attempts will be made to modulate the development of the pathology, and the possible interaction with Abeta will be explored. This project will benefit enormously by being centered in such a comprehensive investigation.